Antagonism between Notch and bone morphogenetic protein receptor signaling regulates neurogenesis in the cerebellar rhombic lip

Robert P. Machold, Deborah Jones Kittell, Gordon Fishell

    Research output: Contribution to journalArticle

    Abstract

    Background: During the embryonic development of the cerebellum, neurons are produced from progenitor cells located along a ventricular zone within dorsal rhombomere I that extends caudally to the roof plate of the fourth ventricle. The apposition of the caudal neuroepithelium and roof plate results in a unique inductive region termed the cerebellar rhombic lip, which gives rise to granule cell precursors and other glutamatergic neuronal lineages. Recently, we and others have shown that, at early embryonic stages prior to the emergence of granule cell precursors (E12), waves of neurogenesis in the cerebellar rhombic lip produce specific hindbrain nuclei followed by deep cerebellar neurons. How the induction of rhombic lip-derived neurons from cerebellar progenitors is regulated during this phase of cerebellar development to produce these temporally discrete neuronal populations while maintaining a progenitor pool for subsequent neurogenesis is not known. Results: Employing both gain- and loss-of-function methods, we find that Notch I signaling in the cerebellar primordium regulates the responsiveness of progenitor cells to bone morphogenetic proteins (BMPs) secreted from the roof plate that stimulate the production of rhombic lip-derived neurons. In the absence of Notch I, cerebellar progenitors are depleted during the early production of hindbrain neurons, resulting in a severe decrease in the deep cerebellar nuclei that are normally born subsequently. Mechanistically, we demonstrate that Notch I activity prevents the induction of Math I by antagonizing the BMP receptor-signaling pathway at the level of Msx2 expression. Conclusion: Our results provide a mechanism by which a balance between neural induction and maintenance of neural progenitors is achieved in the rhombic lip throughout embryonic development.

    Original languageEnglish (US)
    Article number5
    JournalNeural Development
    Volume2
    Issue number1
    DOIs
    StatePublished - Aug 2 2007

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    Bone Morphogenetic Protein Receptors
    Neurogenesis
    Lip
    Neurons
    Cerebellar Nuclei
    Rhombencephalon
    Embryonic Development
    Stem Cells
    Fourth Ventricle
    Bone Morphogenetic Proteins
    Cerebellum
    Maintenance
    Population

    ASJC Scopus subject areas

    • Developmental Neuroscience

    Cite this

    Antagonism between Notch and bone morphogenetic protein receptor signaling regulates neurogenesis in the cerebellar rhombic lip. / Machold, Robert P.; Kittell, Deborah Jones; Fishell, Gordon.

    In: Neural Development, Vol. 2, No. 1, 5, 02.08.2007.

    Research output: Contribution to journalArticle

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